Abstract
The anti-inflammatory drug, PMX205, is an antagonist of the C5a complement receptor and has been shown to be effective in rodent models of amyotrophic lateral sclerosis and Alzheimer’s disease. This cyclic hexapeptide (c[Arg-Trp-D-Cha-Pro-Orn]-Hca) has been reported to produce relatively low yields for both the linear peptide assembly and the cyclization reaction in solution and solid phase syntheses. During attempts to reproduce the solid phase methodology, a catastrophic loss of substitution was encountered which could be avoided or reduced by the use of 2-chlorotrityl resin. Likewise, the cyclization reaction could be significantly improved by the use of FDPP (pentafluorophenyl diphenylphosphinate) at high dilution (up to 80% purified yield). Both improvements are accomplished with commercially available products.
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Abbreviations
- Boc:
-
tert-Butyloxycarbonyl
- COMU:
-
4-[[[(1-cyano-2-ethoxy-2-oxoethylidene)amino] oxayl](dimethylamino)methylene]morpholinium hexafluorophosphate
- DBU:
-
1,8-diazabicyclo[5.4.0]undec-7-ene
- D-Cha:
-
D-cyclohexylalanine
- DEAE:
-
Diethylaminoethyl
- Dde:
-
N-(1-(4,4-dimethyl-2,6-dioxocyclohexylidene)ethyl)
- DIPC:
-
Diisopropylcarbodiimide
- DIPEA:
-
N,N-diisopropylethylamine
- DMF:
-
Dimethylformamide
- ESI–MS:
-
Electrospray ionization mass spectroscopy
- FDPP:
-
Pentafluorophenyl diphenylphosphinate
- Fmoc:
-
9-fluorenylmethyloxycarbonyl
- fw:
-
Formula weight
- GC-MS:
-
Gas chromatography mass spectrometry
- HATU:
-
N-[(dimethylamino)-1H-1,2,2-triazolo[4,5-b]pyridine-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate
- Hca:
-
Hydrocinnaminic acid
- HOAt:
-
1-hydroxy-7-azabenzotriazole
- MTBE:
-
Methyl tert-butyl ether
- mw:
-
Molecular weight
- Pbf:
-
2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-sulfonyl
- PyBOP:
-
Benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate
- RP-HPLC:
-
Reversed phase high performance liquid chromatography
- TFA:
-
Trifluoroacetic acid
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Acknowledgments
We are grateful to the National Institutes of Health (NINDS, NS35144, A.J. Tenner, PI) for partial support (to ARC) of this work. We thank J. Greaves and S. Sorooshian of the UCI Mass Spectrometer Facility for assistance and C.G. Glabe for his support.
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deLisle Milton, R.C., Milton, S.C. & Chamberlin, A.R. Improving the Fmoc Solid Phase Synthesis of the Cyclic Hexapeptide Complement C5a Antagonist, PMX205. Int J Pept Res Ther 17, 337 (2011). https://doi.org/10.1007/s10989-011-9273-9
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DOI: https://doi.org/10.1007/s10989-011-9273-9